This invention relates to azabicyclic compounds. More particularly it relates to pyridone-fused azabicyclic compounds of the formula I below Compounds of formula I are useful in the treatment of addictive disorders such as the use of tobacco or other nicotine containing products and also for the treatment or prevention of withdrawal symptoms caused by cessation of chronic or long term use of tobacco products. These compounds are also useful in the treatment of Huntington""s Chorea, tardive dyskinesia, hyperkinesia, mania, dyslexia, schizophrenia, analgesia, attention deficit disorder (ADD), multi-infarct demetia, age related cognitive decline, epilepsy, neurological and mental disorders related to a decrease in cholinergic function such as Huntington""s Chorea, tardive dyskinesia, hyperkinesia, mania, dyslexia, schizophrenia, analgesia, attention deficit disorder (ADD), multi-infarct demetia, age related cognitive decline, epilepsy, neurological and mental disorders related to a decrease in cholinergic function, senile dementia of the Alzheimer""s type, Parkinson""s disease, attention deficit hyperactivity disorder (ADHD), anxiety, obesity, Tourette""s Syndrome and ulcerative colitis.
The compounds of this invention may also be used in combination with a anti-depressants such as imipramine in order to treat both the cognitive decline and depression associated with AD; in combination with serotonin uptake inhibitors such as Zoloft to treat both the cognitive decline and depression associated with AD; in combination with muscarinic agonists in order to stimulate both central muscarinic and nicotinic receptors; in combination with neurotrophic factors such as NGF in order to maximize cholinergic enhancement; in combination with agents which slow or arrest AD such as amyloid or tau inhibitors.
Substances which can deliver pharmacologically relevant amounts of nicotine to the central nervous system are among the most abused substances known. These include, but not are not limited to tobacco cigarettes, and xe2x80x9cchewing tobaccoxe2x80x9d (see J. E. Henningfield, Ph.D, New England Journal of Med., 1196, 1995). Cigarette smoking has been tied to increased risk for lung cancer, emphysema and heart disease and it is estimated 400,000 people will die in 1995 from the combined effects of nicotine abuse in the United States (see J. A. Califano, Jr., New England Journal of Med. 1214, 1995). Nicotine is a highly addicting drug with 40% of those who try smoking later becoming physically dependent upon it. Attempts to quit the use of nicotine, such as in smoking, have been largely ineffective with  greater than 80% of such attempts ending in failure. Most attempts to quit end in failure in the first week due to intense withdrawal and craving symptoms. An effective therapy should aid in the cessation or lessening of tobacco use, prevent withdrawal, etc. prevent withdrawal symptoms, relieve craving and, simultaneously, antagonize the reinforcing effects of nicotine obtained through smoking. Currently, few therapies are available for smoking cessation and most involve replacement of cigarettes with nicotine in the form of a patch or gum. A high rate of relapse and low overall success in ending nicotine use is evidence of the need for additional and more effective therapies for treatment of nicotine addiction than the nicotine patch or gum.
Pharmaceutical compositions employed for the treatment of chronic nicotinism and addiction to nicotine can be divided into two groups The first covers salts of silver, iron and copper. These substances are employed to develop a negative reflex to smoking usually in the form of a solution, or by incorporation in chewing gum compositions. The resultant reflex is based on the appearance of a strong unpleasant taste in the mouth during smoking after a preliminary rinsing of the mouth cavity with solutions of salts, or after the use of a chewing gum containing such salts (See Nasirov a al. xe2x80x9cAnabasine Hydrochloridexe2x80x94New Antismoking Agentxe2x80x9d, Chemico-Pharmaceutical Journal, vol XII, 1978, No. 2, 149-152).
The second group of agents that are used for the suppression of nicotine addition comprises substances of an alkaloidal nature, such as 1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one (hereafter cytisine), lobeline and anabasine hydrochloride, possessing an effect on H-cholinoreactive systems of the organism similar to that of nicotine. The mechanism of their effect is due to their structural similarity with nicotine and the possible xe2x80x9ccompetitivexe2x80x9d antagonism between these alkaloids and nicotine (F. R. Khalikova, S. H. Nasirov, xe2x80x9cOn pharmacology of the Alkaloid Anabasine and some Polymeric and Copolymeric Derivatives Thereofxe2x80x9d, in Coll. xe2x80x9cPharmacology of Vegetable Compoundsxe2x80x9d, Proceedings of Tashkent University, 457, 1973, 5-16).
U.S. Pat. No. 4,971,079 describes a composition comprising a biologically resorbable polymer containing a cation exchange group modified by an antinicotine action alkaloid, such as anabasine or cytisine, and a gum containing same. However, it has been found that the potency of cytisine is not high due to its inability to penetrate the brain barrier. (Reavill. C. et al., Behavioural and Pharmacokinetic Studies On Nivotine Cytisine and Lobeline, Neuropharmacology, 29, 619-624 (1990)). Labadie L. C. ((Peut-on supprimer les facteurs de risque en bronchopatie chronique et en particulier le tabacxe2x80x9d, Mediater, med, 1976, 4, No. 112, 97, 99)) describes the use of leaves of other night-shade plants, such as potato, tomato, eggplant and digitalis as tobacco substitutes.
One of the most successful approaches to date in reducing the incidence of smoking relies upon nicotine containing chewing gum which is designed to reduce smoking withdrawal symptoms. The reported success rate, while still relatively low, is approximately twice that of the other methods which have heretofore been employed. (See British Medical Journal, 286, (1983)).
The use of the nicotine gum suffers from several problems including bad taste, destruction of dental appliances and gastrointestinal discomfort thereby reducing their use to suppress nicotine addiction. In addition, it has been found that the nicotine containing gum does not completely satisfy the craving that most smokers experience for nicotine and often nicotine gum becomes addictive to the patient.
A simulated smoking device which uses a source of vaporizable nicotine is claimed in U.S. Pat. No 4,284,089 While the cigarette itself is non-combustible it delivers a nicotine-containing vapor which may not raise the nicotine level in the blood sufficiently to satisfy a smoker Thus, it has not been shown to satisfy the desire for a certain nicotine level in the blood to which many smokers have become accustomed and, even more so, upon which many smokers have become dependent. In addition, the simulated smoking devices of the type taught in U.S. Pat. No. 4,284,089 also suffer from the bad taste of a substantial amount of nicotine introduced into the oral cavity. More importantly, this nicotine does not penetrate into the chest for stimulating and providing that sensation normally provided by nicotine and to which the smoker has become accustomed.
The current first line therapy for smoking cessation, as described in U.S. Pat. No. 5,016,652 describes a transdermal patch which is useful for the controlled delivery of nicotine to the bloodstream of the user thereby reducing the incidence of smoking. Clinical trials have shown that abstinence rates (with the nicotine patch) of 30 to 40% can be achieved during the first six weeks of application (K. J. Palmer, M. M. Buckley, D. Faulds, Drugs 44(3) 498-529, (1992) compared with 4 to 21% with a placebo. However, long term abstinence rates ( greater than 6 months) are considerably lower, falling to between 11-18%. Thus, a more effective therapy which will afford a greater percentage of smokers who are able to quit is clearly needed.
This invention relates to pyridone-fused azabicyclic compounds of the formula 
its enantiomers, diastereomers and stereoisomers, and their pharmaceutically acceptable salts and prodrugs,
wherein R1 and R2 are each independently selected from
a) H, halo, CF3, hydroxy, (C1-C6)alkoxy, CH2OH, xe2x80x94C(O)R wherein Rxe2x95x90H, (C1-C6) alkyl, aryl and benzyl including substituted alkyl, aryl and benzyl, Cxe2x95x90xe2x80x94N, Cxe2x95x90xe2x80x94CR, wherein Rxe2x95x90H, (C1-C6) alkyl, aryl including substituted alkyl, aryl. xe2x80x94S(O)nR, wherein Rxe2x95x90H, (C1-C6) alkyl, aryl including substituted alkyl, aryl and n=0, 1, 2. (C1-C6)alkyl, (C1-C6)alkenyl, H2N, di-[(C1-C6)alkyl]amino, (C1-C6)monoalkylamino, (C6-C10)arylamino, (C3-C8)cycloalkylamino, heteroarylamino, cycloheteroalkyamino and CON(R5)2 wherein each R5 is selected from hydrogen, (C1-C8)alkyl and (C6-C10)aryl; and
b) CO2R wherein R is selected from H, (C1-C6)alkyl, phenyl and benzyl; and
c) optionally benzene-fused (C6-C10)aryl, optionally benzene-fused (C3-C8)cycloalkyl, optionally benzene-fused heteroaryl and optionally benzene-fused cycloheteroalkyl, wherein said heteroaryl group contains five to ten atoms comprising one to four heteroatoms, said cycloheteroalkyl contains 4 to 8 atoms comprising one or two heteroatoms selected from N, S and O;
and wherein any of the alkyl, alkenyl, aryl, cycloalkyl, cycloheteroalkyl and heteroaryl groups in a), b) and c) are optionally substituted with one or more substituents selected from halogen, (C1-C6)alkyl, (C6-C10)aryl, hydroxy, hydroxymethyl, CHO and CO2R wherein R is as described above; and
R3 is selected from H, optionally substituted benzyl and methyl;
with the provisos that R1 and R2 are not both hydrogen and when R3 is H, then R1 and R2 when selected from H, Br and Cl, cannot be the same.
In the above compounds, xe2x80x9carylxe2x80x9d includes, without limitation, optionally substituted phenyl and naphthyl, xe2x80x9ccycloalkylxe2x80x9d includes, without limitation, optionally substituted cyclopentyl and cyclohexyl, and said cycloalkyl group may also be unsaturated, and xe2x80x9cheteroarylxe2x80x9d includes, without limitation, thienyl, furyl, pyrano, pyrrolo, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, triazolyl, pyrazinyl and pyridyl, and said xe2x80x9ccycloheteroalkylxe2x80x9d includes, without limitation, pyrrolidinyl, piperidinyl tetrahydrofuryl and tetrahydropyrano.
Preferred compounds of formula I are those wherein R3 is selected from H, benzyl or methyl and R1 and R2 are each independently selected from H, halo, (C1-C6)alkyl, cyano, (C6-C10)aryl, (C5-C9)heteroaryl, (C1-C6)alkenyl, (C2-C6)alkynyl-R and xe2x80x94C(O)R wherein R is H, (C1-C6) alkyl, (C5-C10) aryl and (C5-C9)heteroaryl and amino and mono and di-substituted amino; with the provisos that when R3 is H then R1 and R2 are not both H, Br and Cl and when R3 is benzyl or methyl then R1 and R2 are not hydrogen.
More preferred compounds of formula I are those wherein R1 and R2 are each independently selected from H, ethyl, methyl, phenyl, vinyl, fluoro, bromo, chloro, isopropyl, tert-butyl, trifluoromethyl, acetyl, propanoyl, 2,2-dimethylpropanoyl, 2-methylpropanoyl, butanoyl, pentanoyl, cyano, di-[(C1-C6)alkyl]amino, (C1-C6)monoalkylamino, (C6-C10)arylamino, (C3-C8)cycloalkylamino, heteroarylamino, cycloheteroalkyamino and CON(R5)2 wherein each R5 is selected from hydrogen, (C1-C6)alkyl and (C6-C10)aryl; (C6-C10)aryl and (C5-C9)heteroaryl wherein the aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halogen, (C1-C6)alkyl, (C6-C10)aryl, hydroxy, hydroxymethyl, CHO and CO2R.
More preferred compounds of formula I are those wherein R3 is selected from optionally substituted benzyl or (C1-C6)alkyl, wherein the substituents are described above and R1 and R2 are each independently selected from hydrogen, halo, cyano, optionally substituted (C1-C6)alkyl, (C1-C6)alkenyl, amino, di-[(C1-C6)alkyl]amino, (C1-C6)monoalkylamino, (C6-C10)arylamino, (C3-C8)cycloalkylamino, heteroarylamino, cycloheteroalkyamino and CON(RS)2 wherein each R5 is selected from hydrogen, (C1-C6)alkyl and (C6-C10)aryl; xe2x80x94C(O)R wherein R is H, (C1-C6) alkyl, (C5-C10) aryl and (C5-C9)heteroaryl; (C6-C10)aryl or (C5-C9)heteroaryl wherein the substituents are described above.
More particularly, the invention relates to compounds of the formula I wherein R1 and R2 are each independently selected from hydrogen isopropyl, tert-butyl, trifluoromethyl, acetyl, propanoyl, 2,2-dimethylpropanoyl, 2-methylpropanoyl, butanoyl, pentanoyl, cyano, 2,4-difluorophenyl, 2-fluorophenyl, 2- and 3-thienyl, dimethylamino and R3 is selected from hydrogen, benzyl, methyl and R1 and R2 are each independently selected from hydrogen, bromo, chloro, ethyl, methyl, fluoro, vinyl and phenyl.
Most preferred compounds of the formula I are selected from
9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
11-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
11-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-flouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
11-flouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9,11-diflouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
11-ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8one;
9,11-diethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8one;
11-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9,11-dimethyl-1,2,3,4,5,6-hexahydro-1,2-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
11-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9,11-diphenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-vinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
11-vinyl-1,2,3,4,5,6hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9,11-divinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-bromo-3-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5 ]diazocin-8-one, and
3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one.
Most preferred compounds of the formula I are selected from:
9-morpholino-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-benzylamino-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one,
9-pyrrolidino-1,2,3,4,5,6hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-4-one;
9-dimethylamino-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8one;
9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-tetrahydrofuranyl)-1,2,3,4,5,6-hexahydro-1,5methano-pyrido[1,2a][1,5]diazocin-8-one
9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-ethynyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-propenyl)-1,2,3,4,5,6-hexahydro-1,2-methano-pyrido[1.2a][1,5]diazocin-8-one;
9-(2-propyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-methoxyphenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-[2-(1,1,1-trifluoromethylpropenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(4-methoxyphenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-ethoxy-5-methylphenyl)-1,2,3,4,5,6-hexahydro-1,2-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-benzofuranyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-thienyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(3-thienyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(3-(4-methylthienyl)]-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-[2-(3-methylthienyl)]-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-[3-(2-fluoropyridyl)]-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-pyridyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a[1,5]diazoin-8-one;
9-(2-furanyl)-1,2,3,4,5,6-hexahydro-1,2-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(3-furanyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-trifluoromethylphenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(4-trifluoromethylphenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
11-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,5a][1,5]diazocin-8-one;
9-(2-methylphenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(3-acetylphenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-chlorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(3,4-dichlorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(4-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(3-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2,4-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,2-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-fluoro-4-chlorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-fluoro-4-methoxyphenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8one;
9-(2,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-thiazoyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
The invention also relates to compounds of the formula 
wherein P is defined as R3 or is selected from t-butoxycarbonyl (t-BOC), acetyl, benzoyl, trifluoroacetyl and carbobenzyloxy (CBZ) and R1 and R2 are each independently selected from H, halo, boronic acid, carboalkoxy, carboxyaldehyde, cyano, ethynyl, acyl, 2-propenyl, amino, mono and dialkylamino, aryl and heteroaryl with the proviso that R1 and R2 are not both hydrogen.
Preferred compounds of the formula III, as described above, are those wherein P is t-BOC, acetyl and trifluoroacetyl and each R1 and R2 is independently selected from hydrogen, fluoro, bromo, chloro, iodo, (C1-C6)alkyl, carboalkoxy, carboxyaldehyde, cyano, acetyl, propanoyl, 2,2-dimethylpropanoyl, 2-methylpropanoyl, butanoyl, pentanoyl, 2-propenyl, dimethylamino, with the proviso that R1 and R2 are not both hydrogen.
Most preferred compounds of formula III are selected from:
N-t-BOC-9-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-t-BOC-9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-cBz-9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-trifluoroacety-9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-trifluoroacety-9-bromo-1,2,3,4.5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-acetyl-9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-t-BOC-9-boronic acid -1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-acetyl-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-t-BOC-9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-trifluoroacety-9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-cBz-9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-acetyl-9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-t-BOC-9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-t-BOC-9-ethynyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-t-BOC-9-dimethylamino-1,2,3,4,5,6-hexahydro-1,2-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-t-BOC-9-(2-propenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-t-BOC-9-(2-propyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-t-BOC-9-(2-(1,2-propanediol)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8one;
N-t-BOC-9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-t-BOC-9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
N-t-BOC-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
N-t-BOC-11-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
N-t-BOC-9,11-dibromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one (9,11-dibromo-t-BOC-cytisine);
N-t-BOC-9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
N-t-BOC-11-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
N-t-BOC-9,11-dichloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
N-t-BOC-9-flouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
N-t-BOC-11-flouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one; and
N-t-BOC-9,11-diflouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
The invention also relates to compounds of the formula 
wherein R4 is H, P is is selected from t-butoxycarbonyl (t-BOC), acetyl, benzoyl, trifluoroacetyl and carbobenzyloxy (CBZ), and R1 and R2 are each independently selected from H, (C1-C6)alkyl, (C1-C6)alkenyl and (C6-C10)aryl, with the proviso that R1 and R2 are not both hydrogen.
More particularly, the invention provides compounds of formula II, as described above, wherein R1 and R2 are each independently selected from H, ethyl, methyl, vinyl and phenyl.
Most preferred compounds of formula II are selected from
N-t-BOC-11-vinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8one (11-vinyl-t-BOC-cytisine);
N-t-BOC-11ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one (11-ethyl-t-BOC-cytisine); and
N-t-BOC-11-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one (11-phenyl-t-BOC-cytisine).
Unless otherwise indicated, the term xe2x80x9chaloxe2x80x9d, as used herein includes fluoro, chloro, bromo and iodo.
Unless otherwise indicated, the term xe2x80x9calkylxe2x80x9d, as used herein, may be straight, branched or cyclic, and may include straight and cyclic moieties as well as branched and cyclic moieties.
Unless otherwise indicated, the term xe2x80x9cone or more substituentsxe2x80x9d, as used herein, refers to from one to the maximum number of substituents possible based on the number of available bonding sites.
The term xe2x80x9cone or more carbons of said non-aromatic ringxe2x80x9d, as used herein, refers to from one to all of the carbon atoms that are part of the non-aromatic ring of any of the, aryl-fused or heteroaryl-fused systems described above, and not part of the aromatic ring of said aryl-fused system.
The term xe2x80x9cone or more carbons of said aromatic ringxe2x80x9d, as used herein, refers to from one to all of the carbon atoms that are part of the aromatic ring of any of the aryl-fused and heteroaryl-fused systems described above.
The compounds of formula I have optical centers and therefore may occur in different enantiomeric configurations. The invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of formula I, as well as mixtures thereof.
The present invention also relates to all radiolabelled forms of the compounds of the formulae I. Preferred radiolabelled compounds of formula I are those wherein the radiolabels are selected from as 3H, 11C, 14C, 18F, 123I and 125I. Such radiolabelled compounds are useful as research and diagnostic tools in metabolism pharmacokinetics studies and in binding assays in both animals and man.
The present invention also relates to a pharmaceutical composition for use in reducing nicotine addiction or to aid in the cessation or lessening of tobacco use in a mammal comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt or prodrug thereof, effective in reducing nicotine addiction or to aid in the cessation or lessening of tobacco use and a pharmaceutically acceptable carrier.
The present invention also relates to a method for reducing nicotine addiction in a mammal, comprising administering to a mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt or prodrug thereof, effective in reducing nicotine addiction or lessing of tobacco use.
Examples of pharmaceutically acceptable acid addition salts of the compounds of formula I are the salts of hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, maleate, di-p-toluoyl tartaric acid, and mandelic acid.
Except where otherwise stated, R, R1, R2 and R3, and formulae I, II, III, IV and V, in the reaction schemes and discussion that follow are defined as above 
In each of the reactions discussed below, or illustrated in Schemes 1-3, above, pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 5 atmospheres are generally acceptable, with ambient pressure, i.e., about 1 atmosphere being preferred as a matter of convenience.
Referring to Scheme 1, compound V (cytisine, when R1, R2 and R3 are all hydrogen) is protected to form the compound of the formula IV wherein P is an appropriate nitrogen protecting group, as known in the art, including t-BOC, CBZ, methyl, benzyl, trifluoroacetyl, acetyl and benzoyl. If desired, the N-protection step may be eliminated Compound IV (or V wherein R3 is methyl or benzyl) is halogenated to form a mixture of halogenated products of the formula III wherein one or both of R1 and R2 is a halogen atom, depending upon the conditions and the reaction stoichiometry, preferably iodo, bromo or chloro. Thus, when using one molar equivalent of a suitable halogenating agent, products IIIA and IIIB predominate. However, when two molar equivalents of halogenating agent are used compound IIIC predominates. The nitrogen can be protected by acetyl and trifluoroacetyl, t-BOC, CBZ, benzyl, methyl or any of the readily removable N-protecting groups known in the art. Alternatively, no protecting group need be used.
The t-BOC group can be introduced using a reagent such as di-t-butyldicarbonate, di-t-butylpyrocarbonate, 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile (t-BOC-ON), t-BOC-azide, t-BOC-chloride, t-BOC-fluoride and 2-(t-butoxycarbonyloxy)phthalimide or similar reagents wherein t-BOC refers to the residue tertiary butoxycarbonyl a useful protecting group. The reaction is conducted in a suitable solvent or mixture of solvents, including, but not limited to the following methylene chloride, ethyl acetate, chloroform, benzene, toluene, ether, tetrahydrofuran (THF), dichloroethane and water with a suitable base including, but not limited to, the following: sodium, lithium and potassium carbonates, bicarbonates and hydroxides, imidazole, dimethylaminopyridine and trialkylamines such as triethylamine. The reaction requires 0.5 to 24 hours for completion. The temperature is not critical, the reaction being run between room temperature and the reflux temperature of the solvent or mixture of solvents. The reaction is generally run at a pressure between 0.5 and 2.0 atmospheres, preferably at atmospheric pressure. It is preferably carried out at reflux for 1-2 hours with t-BOC dicarbonate in a mixture of methylene chloride and water with sodium bicarbonate as base. If the protecting group is CBZ (carbobenzyloxy) it can be incorporated by the general procedure described above beginning with the compound of the formula V and carbobenzyloxy chloride (CBZxe2x80x94Cl) instead of the t-BOC source.
Referring to Scheme 3, the N-methyl or N-benzyl group can be introduced by nitrogen alkylation of cytisine or the compound of the formula I (or V when R3 is hydrogen) with a suitable reagent. Suitable reagents for N-benzylation include benzyl halides, such as the bromide, chloride and iodide and sulfonic acid esters such as the mesylate, tosylate and triflate in an inert solvent such as dimethylformamide (DMF), N-methylpyrrolidone, dimethylsulfoxide (DMSO), acetone, ethanol, methanol, acetonitrile, THF and water and mixtures thereof with a base such as sodium or potassium hydride, 1,8-diazobicyclo[5 4 0]undec-7-ene (DBU), potassium t-butoxide, tri(C1-C6)alkylamines such as triethylamine, sodium, lithium and potassium carbonates, bicarbonates and hydroxides, imidazole and dimethylaminopyridine. Aprotic solvents must be used when the bases, such as the hydrides, are reactive to protic solvents such as water The reaction can be run at temperatures between 0xc2x0 C. and the reflux temperature of the solvent for a period of 0.5 hours to 48 hours. It is preferably carried out with benzyl chloride in acetone at reflux for 1-2 hours using potassium carbonate as base at atmospheric pressure.
For N-methylation, suitable reagents are methyl iodide or bromide, dimethylsulfate and methyl triflate using the conditions described above for N-benzylation. The reaction is preferably carried out with methyl iodide in acetone at reflux for 1-2 hours using potassium carbonate as base.
Alternatively, N-benzylation may be carried out in the following manner. The compound of formula I (or V wherein R3 is hydrogen), in an inert solvent, such as (C1-C6)alkanols, preferably methanol or ethanol, and halocarbons such as methylene chloride, chloroform and dichloroethane and acetic acid and water and mixtures thereof, is treated with benzaldehyde and a reducing agent such as sodium triacetoxyborohydride, tetraalkylammonium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride or similar reagents with or without a catalytic amount of an acid, such as acetic acid or trifluoroacetic acid at a temperature between 0xc2x0 C. and the reflux temperature of the solvent, or mixture of solvents, for a period of 0.5 to 48 hours at atmospheric pressure. The reaction is preferably carried out in dichloroethane at room temperature with benzaldehyde, sodium triacetoxyborohydride and a catalytic amount of acetic acid for a period of two hours.
N-Methylation can, alternatively, be carried out with a source of formaldehyde such as formaldehyde gas, formalin, paraformaldehyde or trioxane and a suitable reducing agent, as described above, in an inert solvent, as described above or, alternatively, in a solvent such as refluxing formic acid without a separate reducing agent. When the source of formaldehyde is trioxane the reaction must be effected in the presence of an acid such as the the formic acid, above. N-Methylation can also be carried out in an inert solvent such as methanol, ethanol or water in the presence of a source of formaldehyde and a palladium catalyst, such as palladium on carbon, under 1-10 atm. of hydrogen gas for a period of 1-24 hours.
Acylation of the secondary nitrogen with either acetyl chloride, acetic anhydride or trifluoroacetic anhydride may be carried out in a suitable inert solvent or mixture of solvents such as methylene chloride, dichloroethane, acetonitrile, toluene, benzene, ethyl acetate, chloroform, ether water or THF. Usually an equivalent of base or an excess of base is used. Bases such as pyridine, triethyl amine, diisopropylethylamine, sodium or potassium carbonate or bicarbonate, hydroxides, imidazole, or dimethylaminopyridine may be used interchangeably. In some or all cases, the base may be used as the solvent as in the case of pyridine or aqueous carbonate solutions. The temperature is not critical but is generally held between xe2x88x9220xc2x0 C. and ambient. The reaction requires 0.5 to 24 hours for completion Most preferably, the acylating agent is acetic anhydride or trifluoroacetic anhydride in a solvent such as dichloromethane with a base such, as pyridine at 0xc2x0 C. to room temperature for 1 hour.
Referring to Scheme 1 bromination of compound IV (or V when R3 is methyl or benzyl) is carried out in an inert solvent such as methylene chloride, ethyl acetate, chloroform, benzene, toluene, tetrahydrofuran (THF) with a brominating reagent such as bromine, N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin, N-bromoacetamide or similar reagents. The reaction can be carried out at atmospheric pressure with or without a suitable inert base such as sodium, lithium or potassium bicarbonate and tri(C1-C6)alkylamines such as triethylamine at temperatures between ambient and the reflux temperature of the solvent at atmospheric pressure for a period of 0.5 to 24 hours. It is preferably carried out with NBS in methylene chloride at reflux for 1.5 hours.
Chlorination of compound IV is effected, under the conditions described above for the bromination reactions including use of the same solvents and water, by treatment with a chlorinating reagent such as chlorine, N-chlorosuccinimide (NCS) and N-chloroacetamide or a similar reagent at temperatures between 0xc2x0 C. and the reflux temperature of the solvent at atmospheric pressure for a period of 0.5 to 24 hours. It is preferably carried out with NCS in methylene chloride at reflux for 1-2 hours or chlorine in water at 0xc2x0 C. for 1-2 hours.
Iodination of compound IV is effected under the conditions described above for chlorination or bromination. This includes the use of the same solvents and water by treatment with an iodinating agent such as N-iodosuccinimide, iodine or ICI or a similar reagent. The iodination is conducted at a temperature between 0xc2x0 C. and the reflux point of the solvent while at atmospheric pressure for a period of 0.5-24 hours. Alternatively it is carried out in methanol or methanol-methylene chloride with a suitable carbonate base such as sodium, potassium, magnesium or calcium carbonates. It is preferably carried out in methanol-methylene chloride with ICI and a base such as calcium carbonate.
The halogenation reactions generally produce a mixture of mono and dihalogenated products depending upon the exact conditions of time, temperature and reagents. These may be varied to favor a particular substitution pattern as detailed in the experimental section. The mixture can be purified to a single product by crystallization or trituration from a solvent or mixture of solvents such as diethyl ether, isopropylether and ethyl acetate-hexanes. Alternatively, the mixture may be separated -by chromatography on silica gel or another support eluting with a mixture of methylene chloride or chloroform or ethyl acetate with methanol or similarly with mixtures of ethyl acetate with hexanes. It is preferably separated through crystallization from diethyl ether or mixtures of diethyl ether and another solvent such as hexane or by chromatography on silica gel eluting with a mixture of methylene chloride and methanol.
Scheme 2 illustrates the further transformation compound III, as exemplified by compound IIIA, wherein R2 is hydrogen and R1 is bromo or iodo, to the compound of the formula IIA (Although the following procedures are discussed with respect to the compounds of the formulae IIIA, IIA, and IA they are equally applicable to the B and C counterparts thereof). Thus, replacement of the bromo or iodo atom by optionally substituted (C1-C6)alkyl or (C1-C6)alkenyl or (C6-C10)aryl may be carried out by reaction of the bromide or iodo or dibromide with an organometallic compound such as tetra(C1-C6) alkyltin, (C1-C6)alkenyltri-(C1-C6)alkyltin or phenyltri(C1-C6)alkyltin under the influence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium, transbenzylchlorobis (triphenylphosphine)palladium, palladium on carbon, palladium acetate, palladium chloride, palladium trifluoroacetate, palladium trisdibenzylideneacetone, bis (triphenylphoshine)palladium dichloride or other sources of coordinated palladium (0) or palladium (II). The reaction can be carried out in a solvent such as hexamethylphosphoramide (HMPA), N-methylpyrrolidone, ethanol, methanol, water or DMF at temperatures from ambient to 130xc2x0 C. for 6-48 hours at 1-2 atmospheres pressure. Alternatively, the organometallic reagent can be a (C1-C6)alkyl, (C1-C6)alkenyl or arylzinc halide wherein halide refers to chloride, bromide and iodide. The organometallic reagent can also be a (C1-C6) alkyl ester of a (C1-C6)alkyl, (C1-C6)alkenyl, (C6-C10)aryl or (C6-C10)heteroaryl boronic acid. The most preferred conditions involve reaction of the bromide or dibromide with an organotin compound such as tetramethyltin, vinyl(trimethyl)tin, vinyl(tri-n-butyl)tin, phenyl(trimethyl)tin and phenyl(tri-n-butyl)tin in the presence of trans-benzylchlorobis(triphenylphosphine)palladium in HMPA at 40 to 80.0xc2x0 C. for 20 to 40 hours. Other preferred conditions for forming the the compound (group) of the formula II is by treatment of the compound of formula III with the aryl, alkenyl or heteroaryl boronic acid, in a mixture of ethanol and water, in the presence of tetrakis(triphenyl)phosphinepalladium (0) and a suitable base such as sodium, potassium or lithium carbonate or bicarbonate with sodium carbonate generally preferred.
Scheme 4 illustrates the further transformation of compound III as exemplified by compound III A, wherein R2, R4=H and R1 is bromo or iodo, to the compound of formula VI. (Although the following procedures are discussed with respect to the compounds of formulae IIIA, and VI A they are equally applicable to the B and C counter parts thereof.) Thus, replacement of the bromo or iodo atom with carboalkoxy or carboxy may be carried out by the reaction of the bromide or the iodo in an alcoholic solvent such as methanol, ethanol, isopropanol, tert-butanol etc. or alternatively in water with or without a suitable co-solvent such as DMSO or DMF under 1-200 atmospheres of carbon monoxide gas in the presence of catalytic palladium metal with or without a ligand. Sources of palladium such as palladium on carbon, palladium acetate, palladium chloride, palladium trifluoroacetate, palladium tris(dibenzylideneacetone), palladium bis(dibenzylideneacetone) or other sources of ligated palladium (0) such as tetrakis(triphenylphosphine)palladium or palladium (II) salts such as DIS triphenylphoshinepalladium dichloride are effective in this transformation Suitable ligands for this transformation are, 1,3-diphenylphosphinylpropane (dppp), 1,3-diphenylphosphinylethane (dppe) 1,3-diphenylphosphinylbutane (dppb), triphenylphosphine, 2,2xe2x80x2-bis(diphenyl phosphino)-1,1-binaphthyl (BINAP), 1,1xe2x80x2-bis(diphenylphosphino) ferrocene (dppf) or other commercially available bidentate ligands are satisfactory in this transformation. The reaction was conducted in the presence of a suitable base such as sodium, lithium or potassium carbonate, sodium, lithium or potassium bicarbonate or sodium, lithium or potassium hydroxides Temperature of the reaction can vary from room temperature to 100xc2x0 C. for a time of between 1 and 24 hours. Most preferably the reaction is carried out between iodide or bromide IIIA in methanol with palladium acetate and dppp under 16 psi carbon monoxide and potassium bicarbonate for a period of 16 hrs at 70xc2x0 C.
A similar process, as described above for the formation of the ester may be used to produce the carboxamide of the formula XVIIA from a compound of the formula IIIA (R1xe2x95x90I or Br). Thus, replacement of the bromo or iodo atom with a substituted or unsubstituted carboxamide may be carried out by the reaction of the bromide or the iodo under 1-200 atmospheres of carbon monoxide gas in the presence of catalytic palladium metal with or without a ligand using a source of palladium as detailed above. Typically the amine is used as the solvent or if it is a gas then it is used as a staurated solution in an inert solvent. Preferred conditions, using an amine such as benzyl amine as solvent under 50 psi carbon monoxide at 50xc2x0 C. in the presence of catalytic bis-triphenylphosphine palladium (II) chloride for 24 hours. Alternatively, the amide XVIIA may be prepared from VIA under standard conditions of ammonolysis or aminolysis with or without a catalyst Thus a saturated solution of a suitable amine gas in an inert solvent or, if it is a liquid, the neat amine is heated at atmospheric pressure or at an elevated pressure of from 1-5 atmospheres to produce the amide directly. Alternatively, the reaction may be run under mild conditions using a catalyst such as trialkylaluminum or trialkylstannanes.
The ester or carboxylate VI as well as the carboxamide XVIIA may optionally be further transformed to compounds VII, VIII, IX and X by hydride reduction or by addition of a organometallic nucleophile. In the case of VII, at least two equivalents of hydride is needed to reduce VI whereas the formation of VIII only requires the addition of one hydride equivalent. Similarly, In the case of X, addition of at least two equivalents of organometallic are needed to afford X whereas addition of a single equivalent will afford IX. Proper control of experimental conditions can afford mono or bis addition of VI and specific conditions for each transformation are known in the art (for reviews see: O""Neill B. T. in Comprehensive Organic Synthesis; B. M. Trost Editor, Vol 1, 397-458, Pergamon, 1991 or Reductions in Organic Chemistry, 2nd Ed, Hudlicky, M., ACS Washington D.C. 1996). Suitable reducing agents for the process VI to VIII and VII are lithium aluminum hydride, sodium, potassium or lithium borohydride, lithium triethylborohydride, diisobutyl aluminum hydride (DiBAL-H), aluminum hydride, amino-borane lithium salt and similar reagents Generally, these reactions may be conducted in solvents such as THF or diethyl ether, t-butylmethyl ether, diisopropyl ether, toluene, dichloromethane, dichloroethane or dimethoxyethane. The temperature of the reaction may vary but can be run between xe2x88x9278xc2x0 C. and ambient temperature or between ambient temperature and the reflux point of the solvent. The reaction generally requires between 0.5 and 24 hours for completion and generally is run at ambient pressure. Most preferred conditions are DIBAL-H in methylene chloride at xe2x88x9278xc2x0 C. for 3 hours.
Suitable organometallic reagents for the process of VI to IX and X as well as XVII to IX include (C1-C6)alkyl lithiums, (C1-C6)alkyl magnesium halides (wherein halide refers optionally to chloride, bromide or iodide), or (C1-C6)alkyl cuprate or di(C1-C6)alkyl cuprates. More specifically methyl lithium, methyl magnesium halide, t-butyl lithium, t-butyl magnesium halide, isopropyl lithium, isopropyl magnesium halide, n-butyl lithium, n-butyl magnesium halide, s-butyl lithium, s-butyl magnesium halide. Most specifically methyl lithium and methyl magnesium halide. The reaction can be run in several inert solvents such as THF or diethyl ether, dimethoxyethane or similar solvents. The temperature of the reaction may vary but can be run between xe2x88x9278xc2x0 C. and ambient temperature or between ambient temperature and the reflux point of the solvent. The reaction generally requires between 0.5 and 24 hours for completion and generally is run at ambient pressure. The compound of formula X may also be transformed into compounds of this invention by modification of the tertiary alcohol. For example, the compound of formula IX may be obtained through the sequence X to XI to XII followed by conversion directly to IX. This sequence may be completed with or without isolation of the individual intermediates which are themselves a part of the subject matter of this case. Transformation of X to XI may be carried out under acidic conditions or alternatively by first transforming the tertiary alcohol to a suitable leaving group such as a halogen or a group such as a mesylate, triflate, tosylate or other suitable activating group followed by base catalyzed elimination. The reaction under acidic conditions may use one of the following acidic reagents in water with or without a co-solvent acetic, trifluoroacetic, sulfuric, hydrochloric, hydrobromic acid and other similar reagents or alternatively silica gel may be used. Suitable solvents include water, methanol, ethanol, isopropanol, THF or diethyl ether, t-butylmethyl ether, diisopropyl ether, toluene, dichloromethane, dichloroethane chloroform or dimethoxyethane, ethyl acetate acetonitrile or similar solvents or combination of solvents. The transformation from X to XI may be completed at a temperature of 0xc2x0 C. to room temperature for a period of 5 minutes to 5 hours. The most preferred conditions are trifluoroacetic acid in methylene chloride at 0xc2x0 C. to room temperature for a period of two hours.
Conversion of XI to IX may be carried out with or without isolation of the intermediate XII Formation of XII can be accomplished with a reagent such as osmium tetroxide or potassium permanganate in a suitable solvent or combination of solvents such as water, acetone t-butanol dioxane or THF. The osmium tetroxide can be used in catalytic quantities if combined with a second oxidant such as N-methylmorpholine-N-oxide or trimethyl amine N-oxide, triethylamine-N-oxide or sodium periodate. Generally the reaction is carried out at room temperature but may be run between 0xc2x0 C. and the reflux point of the solvent for a period of 12 to 48 hours The most preferred conditions involve the use of catalytic osmium tetroxide with N-methylmorpholine-N-oxide and sodium periodate in dioxane/water at room temperature for 24 hours to afford IX directly. Alternatively, XI may be directly converted to IX with ozone gas under standard conditions. Thus ozone in oxygen may be introduced to a solution of XI in a suitable solvent such as methanol, ethanol, isopropanol, toluene, dichloromethane, dichloroethane chloroform, ethyl acetate and acetonitrile or similar solvents or combination of solvents. The reaction is generally run at xe2x88x9278xc2x0 C. but may also be run between xe2x88x9278xc2x0 C. to ambient temperature for a period of 5 minutes to 1 hour. An indicator such as sudan red may or may not be employed to indicate when the reaction is complete. The reaction is then quenched under reducing conditions to afford the product IX. Suitable reducing agents include but are not limited to dimethyl sulfide, zinc and acetic acid, hydrogen/palladium on carbon, triphenyl phosphine or similar reagents. The most preferred conditions are ozone in methylene chloride at xe2x88x9278xc2x0 C. in the presence of sudan red indicator followed by addition of dimethyl sulfide.
Direct conversion of III A (R1xe2x95x90Br or I) to IX may also be accomplished through halogen metal exchange and acylation. Thus the bromide or iodide IIIA may be treated with a metal such as lithium, sodium, magnesium or zinc to form the corresponding organometallic which is then quenched with a suitable acylating agent. Suitable acylating agents include esters, thioesters, acids, amides, N-methoxy-N-methylamides, anhydrides, acid chlorides and similar agents. The reaction may be initiated by using the metal directly or by prior formation of a metal complex with an aromatic agent such as napthalene or biphenyl such as lithium naphthalide or through the use of an organometallic such as n-butyl lithium, t-butyl lithium, s-butyl lithium, methyl magnesium halide or similar reagents. Suitable solvents for this transformation include THF, ether, dimethoxyethane as well as similar reagents. The most preferred conditions are n-butyl lithium. In THF at xe2x88x9278xc2x0 C. to 0xc2x0 C. using N-methoxy-N-methylamides for 2.5 hours.
Direct conversion of VIIIA to IX A may be accomplished as described above for the conversion of VIA to IX A, however, a second step is required to convert the intermediate secondary alcohol (not shown) in to the ketone. Suitable reagents for this transformation include chromium trioxide and chromium trioxide pyridine complex, pyridium chlorochromate, pyridium dichromate, potassium permanganate, hypochlorous acid, mixtures of DMSO with oxalyl chloride or trifluoracetic anhydride and other well known reagents capable of oxidation of alcohols to ketones.
Scheme 5 illustrates the further transformation of compound III as exemplified by compound III A, wherein R2, R4=H and R1 is bromo or iodo, to the compounds of formula XIII, XIV, XV, XVI. (Although the following procedures are discussed with respect to the compounds of formulae IIIA, and XIII A, XIV A, XV A, XVI A they are equally applicable to the B and C counter parts thereof). Thus, replacement of the bromo or iodo atom with zinc cyanide afforded XIII (Xxe2x95x90N) under palladium catalysis in a polar aprotic solvent such as DMF, DMSO, N,N-dimethylacetamide, N-methyl pyrrolidone or similar solvents at a temperature between ambient temperature and 150xc2x0 C. for a period of 6 to 48 hours at atmospheric pressure. Suitable catalysis include but are not limited to palladium tris(dibenzylideneacetone), palladium bis(dibenzylideneacetone) or other sources of ligated palladium (0) such as tetrakis(triphenylphosphine)palladium or palladium (II) salts such as bistriphenylphoshinepalladium dichloride:, 1,3-diphenyl phosphinylpropane palladium(0) [(dppp)Pd(0)], 1,3-diphenylphosphinyl ethane palladium(0) [(dppe)Pd(0)], 1,3-diphenylphosphinylbutanepalladium(0) [(dppb) Pd(0)], 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl palladium(0) [(BINAP) Pd(0)], 1,1xe2x80x2-bis(diphenylphosphino) ferrocene palladium(0) [(dppf) Pd(0)] or other commercially available palladium sources are satisfactory in this transformation. The most preferred conditions use bromo or iodo IIIA together with zinc cyanide in DMF and tetrakis(triphenylphosphine)palladium (0) at 80xc2x0 C. for 16 hours.
Alternatively, in a similar manner to that described above, one may replace the bromo or iodo atom with an acetylene to afford XIII (Xxe2x95x90CR, wherein Rxe2x95x90H, (C1-C6) alkyl, aryl including substituted alkyl, aryl). Thus treatment as above but with the substitution of an acetylene (such as trimethylsilylacetylene or other acetylenes) for zinc cyanide will lead to the formation of XIII (Xxe2x95x90CR). Typically the reaction is run in a solvent such as diethylamine or pyrrolidine or other secondary amines with a catalyst such as copper (I) iodide, bromide or chloride and in the presence of a palladium catalyst as described above. The reaction is run at a temperature between ambient temperature and the reflux point of the solvent for a period of 1to 24 hours at atmospheric pressure. Typically it is run at ambient temperature for 4 hours.
Substitution of the bromo or iodo atom in III A with a primary or secondary amine R,Rxe2x80x2NH, wherein R and Rxe2x80x2 may be any of H, (C1-C6) alkyl, aryl and benzyl, to afford XIV. Typically, the reaction is conducted in a solvent such as toluene, benzene, xylene, dioxane or THF at a temperature between ambient temperature and the reflux point of the solvent. Typically the reaction is conducted in toluene at about 80xc2x0 C. The reaction is catalyzed with palladium metal in the presence of a suitable ligand. Sources of palladium include but are not limited to palladium acetate, palladium tris(dibenzylideneacetone), palladium bis(dibenzylideneacetone), in the presence of a ligand such as dppp, dppe, dppb, dppf, BINAP, tri-o-tolylphosphine or alternatively tetrakis(triphenylphosphine)palladium, 1,3-diphenylphosphinyl propanepalladium (0) [(dppp)Pd(0)], 1,3-diphenylphosphinyl ethane palladium(0) [(dppe)Pd(0)], 1,3-diphenylphosphinylbutane palladium(0) [(dppb)Pd(0)], 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl palladium(0) [(BINAP) Pd(0)], 1,1xe2x80x2-bis(diphenylphosphino) ferrocene palladium(0) [(dppf) Pd(0)] or other commercially available palladium sources are satisfactory in this transformation. Most preferably 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl palladium(0) [(BINAP) Pd(0)] is used. Typically a base such as sodium, potassium or lithium butoxide or sodium, potassium tert-amyloxide is used in the process. Most preferably sodium t-butoxide is used.
Substitution of the bromo or iodo atom in III A with a sulfide RSH, wherein R may be any of H, (C1-C6) alkyl, aryl and benzyl, to afford XVI (wherein n=0,1,2). Typically, the reaction is conducted in a solvent such as toluene, benzene, xylene, dioxane or THF at a temperature between ambient temperature and the reflux point of the solvent. Typically the reaction is conducted in toluene at about 80xc2x0 C. The reaction is catalyzed with palladium metal in the presence of a suitable ligand. Sources of palladium include but are not limited to palladium acetate, palladium tris(dibenzylideneacetone), palladium bis(dibenzylideneacetone), in the presence of a ligand such as triphenylphosphine, dppp, dppe, dppb, dppf, BINAP, tri-o-tolylphosphine or alternatively tetrakis(triphenylphosphine)palladium, 1,3-diphenylphosphinyl propanepalladium (0) [(dppp)Pd(0)], 1,3-diphenylphosphinyl ethane palladium(0) [(dppe)Pd(0)], 1,3-diphenylphosphinylbutane palladium(0) [(dppb)Pd(0)]. 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl palladium(0) [(BINAP) Pd(0)], 1,1xe2x80x2-bis(diphenylphosphino) ferrocene palladium(0)[(dppf) Pd(0)] or other commercially available palladium sources are satisfactory in this transformation. Most preferably 1,3-diphenylphosphinyl ethane palladium(0) [(dppe)Pd(0)], is used. Oxidation of the newly formed sulfide (wherein n=0) to afford the sulfoxide (wherein n=1) or the sulfone (wherein n=2), may be accomplished under standard conditions for oxidation known in the art. Typically, oxidants such as oxygen, hydrogen peroxide, OXONE, m-chloroperbenzoic acid or other per-acids such as peracetic acid and hypochlorous acid may be used.
Alternatively, substitution of the bromo or iodo atom in III A may be conducted with an alkene or a suitable vinyl ether to form XV A. The olefin or vinyl ether may be part of a ring system or alternatively, it may be part of an acyclic system. Thus R in XV may be simply (C1-C6) alkyl or benzyl or alternatively it may be part of a ring which includes the olefin. The ring size typically contains 5,6,7 or 8 atoms. The reaction is conducted in a suitable polar aprotic solvent such as DMF, DMSO, N,N-dimethylacetamide, N-methyl pyrrolidone or similar solvents at a temperature between ambient temperature and 150xc2x0 C. for a period of 0.5 to 24 hours at atmospheric pressure. Typically the reaction is conducted in DMF at about 90xc2x0 C. The reaction is catalyzed by palladium typically in the form of palladium acetate or palladium dichloride with or without a ligand such as triphenylphosphine, dppp, dppe, dppb, dppf, BINAP, tri-o-tolylphosphine. The reaction may also be run in the presence or absence of a suitable base such as sodium, lithium or potassium acetate, triethyl amine or diisopropylethylamine and alternatively in the presence or absence of teraalkyl ammonium salts such as terabutylammonium chloride, bromide, acetate or iodide. Typically the reaction is conducted between IIIA and dihydrofuran in DMF at about 90xc2x0 C. with palladium acetate, triphenyl phosphine, tera-butyl ammonium acetate, potassium acetate for 16 hours. Also the reaction between III A and butyl vinyl ether is conducted in DMF at 90xc2x0 C. for 1.5 hours using palladium acetate, dppf and triethyl amine The resulting product retains the olefin carbon bond which may undergo further reaction under standard conditions known in the art. These include but are not limited to hydrogenation and also reaction with aqueous acid.
The t-BOC protecting group can be readily removed from the protected products IIIA, IIA, VIA, VIIA, VIIIA, IXA, XA, XIA, XIIA, XVIIA, XVIIIA, XIVA, XVA, and XVIA described above, to form the compound IA (Scheme 2) wherein R3 is hydrogen and R1 is as defined previously respectively, by treatment with an acid such as hydrochloric, sulfuric, trifluoroacetic, acetic, nitric, hydrofluoric, hydrobromic and hydroiodic using water as a solvent or co-solvent or in anhydrous organic solvents such as methanol, ethanol, ether, ethyl acetate, methylene chloride and chloroform or mixtures thereof. The product is obtained as its acid salt which may be then treated with a suitable base including, but not limited to, the following: sodium, lithium and potassium carbonates, bicarbonates and hydroxides, generally, in water to afford the desired material as the free base form.
The benzyl and CBZ protecting groups can be removed from the compounds of formulae IIIA, IIA, VIA, VIIA, VIIIA, IXA, XA, XIA, XIIA, XVIIA, XIIIA, XIVA, XVA and XVIA by treatment, in a solvent such as methanol, water, acetic acid and ethyl acetate, with 1 to 10 atmospheres of hydrogen gas in the presence of a catalyst such as palladium on carbon, palladium hydroxide and palladium hydrochloride, at a temperature from ambient to about 50xc2x0 C.
Compound IA, wherein R3 is hydrogen, can be treated, as described above for N protection, by benzylation or methylation, to form compound IA wherein R3 is benzyl or methyl.
Alternatively, if R3, in compound IA, is to be benzyl or methyl and the protecting group P is benzyl or methyl no deprotection step is needed as compound IA corresponds to compound IIIA, IIA VIA, VIIA, VIIIA, IXA, XA, XIA, XIIA, XVIIA, XIIIA, XIVA, XVA and XVIA. If P is an acyl group such as a trifluoroacetyl group then it may be removed by treatment with dilute acid or base to afford a compound of the formula I. Thus treatment with aqueous sodium bicarbonate, carbonate or hydroxide and a co-solvent such as methanol, ethanol, THF, dioxane or similar inert solvents may be used. Also methanol and sodium methoxide may be used. Alternatively, aqueous acid such as dilute hydrochloric acid may be used in combination with an inert co-solvent as described above. The temperature of the reaction may range from 0xc2x0 C. to the reflux point of the solvent.
The compounds of the formula I and their pharmaceutically acceptable salts (hereafter xe2x80x9cthe active compoundsxe2x80x9d) can be administered via either the oral, transdermal (e.g., through the use of a patch), intranasal, sublingual, rectal, parenteral or topical routes. Transdermal and oral administration are preferred. These compounds are most desirably administered in dosages ranging from about 0.25 mg up to about 1500 mg per day, preferably from about 0.25 to about 300 mg per day in single or divided doses, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.02 mg to about 10 mg per kg of body weight per day is most desirably employed Variations may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.
The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes previously indicated. More particularly, the active compounds can be administered in a wide variety of different dosage forms, e.g., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar] as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration the active ingredient may be combined with various sweetening or flavoring agents, coloring matter and, if so desired, combined with various sweetening or flavoring agents, coloring matter and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
For parenteral administration, a solution of an active compound in either sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8), if necessary, and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
It is also possible to administer the active compounds topically and this can be done by way of creams, a patch, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The effectiveness of the active compounds in suppressing nicotine binding to specific receptor sites is determined by the following procedure which is a modification of the methods of Lippiello, P. M. and Femandes, K. G. (in The Binding of L-[3H]Nicotine To A Single Class of High-Affinity Sites in Rat Brain Membranes, Molecular Pharm., 29, 448-454, (1986)) and Anderson, D. J. and Arneric, S. P. (in Nicotinic Receptor Binding of 3H-Cystisine, 3H-Nicotine and 3H-Methylcarmbamylcholine In Rat Brain, European J. Pharm., 253, 261-67 (1994)).
Male Sprague-Dawley rats (200-300 g) from Charles River were housed in groups in hanging stainless steel wire cages and were maintained on a 12 hour light/dark cycle (7 a.m.-7 p.m. light period). They received standard Purina Rat Chow and water ad libitum.
The rats were killed by decapitation. Brains were removed immediately following decapitation. Membranes were prepared from brain tissue according to the methods of Lippiello and Fernandez (Molec. Pharmacol. 29, 448-454, (1986) with some modifications. Whole brains were removed, rinsed with ice-cold buffer, and homogenized at 0xc2x0 in 10 volumes of buffer (w/v) using a Brinkmann Polytron(trademark), setting 6, for 30 seconds. The buffer consisted of 50 mM Tris HCl at a pH of 7.5 at room temperature. The homogenate was sedimented by centrifugation (10 minutes; 50,000xc3x97 g; 0 to 4xc2x0 C. The supernatant was poured off and the membranes were gently resuspended with the Polytron and centrifuged again (10 minutes; 50,000xc3x97g; 0 to 4xc2x0 C. After the second centrifugation, the membranes were resuspended in assay buffer at a concentration of 1.0 g/100 mL. The composition of the standard assay buffer was 50 mM Tris HCl, 120 mM NaCl, 5 mM KCl, 2 mM MgCl2, 2 mM CaCl2 and has a pH of 7,4 at room temperature.
Routine assays were performed in borosilicate glass test tubes. The assay mixture typically consisted of 0.9 mg of membrane protein in a final incubation volume of 1.0 mL. Three sets of tubes were prepared wherein the tubes in each set contained 50 xcexcL of vehicle, blank, or test compound solution, respectively. To each tube was added 200 xcexcL of [3H]-nicotine in assay buffer followed by 750 xcexcL of the membrane suspension. The final concentration of nicotine in each tube was 0.9 nM. The final concentration of cytisine in the blank was 1 xcexcM. The vehicle consisted of deionized water containing 30 xcexcL of 1 N acetic acid per 50 mL of water. The test compounds and cytisine were dissolved in vehicle. Assays were initiated by vortexing after addition of the membrane suspension to the tube. The samples were incubated at 0 to 4xc2x0 C. in an iced shaking water bath. Incubations were terminated by rapid filtration under vacuum through Whatman GF/B(trademark) glass fiber filters using a Brandel(trademark) multi-manifold tissue harvester. Following the initial filtration of the assay mixture, filters were washed two times with ice-cold assay buffer (5 m each). The filters were then placed in counting vials and mixed vigorously with 20 ml of Ready Safe(trademark) (Beckman) before quantification of radioactivity. Samples were counted in a LKB Wallach Rackbeta(trademark) liquid scintillation counter at 40-50% efficiency. All determinations were in triplicate.
Specific binding (C) to the membrane is the difference between total binding in the samples containing vehicle only and membrane (A) and non-specific binding in the samples containing the membrane and cytisine (B), i.e.,
Specific binding=(C)=(A)xe2x88x92(B).
Specific binding in the presence of the test compound (E) is the difference between the total binding in the presence of the test compound (D) and non-specific binding (B), i.e., (E)=(D)xe2x88x92(B).
% Inhibition=(1xe2x88x92((E)/(C)) times 100.
The compounds of the invention, which were tested, exhibited IC50 values of less than 1 xcexcM.
To a one liter round bottom flask was charged 10 gm (0.053 mmol) (xe2x88x92)-cytisine followed by a mixture of 320 ml methylene chloride and 100 ml water. The two phase mixture was treated with 6.62 gm (0.079 mmol) sodium bicarbonate and finally 12.6 gm (0.058 mmol) di-t-butyl-dicarbonate. The reaction mixture was heated under reflux for 1.5 hours. The mixture was allowed to cool and was then diluted with brine. The organic layer was washed with brine and dried and the solvent evaporated. There was obtained 14.4 gm (94% crude) of the title product which was used directly in the next step. 1H NMR (CDCl3, 250 MHz) xcex47.28 (dd, 1H), 6.45 (d, 1H), 6.05 (d, 1H), 4.19 (m, 3H), 3.81 (dd, 1H), 3.0 (br.s, 3H), 2.41 (br.s, 1H), 1.99 (m, 2H), 1.29 (br.s, 9H) ppm, mass spectrum (thermospray) m/e 291 p+1.